Project Summary/Abstract Age-related cognitive decline gradually devolves into dementia (e.g. Alzheimer disease, AD). Emotional and healthcare burden, and the fact that AD-neuropathology precedes cognitive changes by many years, make the identification of biomarkers of early disease progression critically important. Aspects of AD neurochemistry other than ?-amyloid need to be considered while searching for a reliable biomarker. Glutamate (Glu), the primary excitatory neurotransmitter involved in cognitive processes, is reduced in several key brain regions (specifically the hippocampus, HC) in AD and normal aging. Episodic memory decline is the first cognitive symptom in AD, as well as normal aging. Episodic and associative memory relies on hippocampal Glu. Understanding age-related variations in this system may help track early decline in cognition. Proton functional magnetic resonance spectroscopy (1H fMRS) is the only non-invasive neuroimaging technique that can detect in vivo levels of Glu. We have recently demonstrated that 1H fMRS can detect the temporal dynamics of hippocampal Glu in healthy young adults, which in turn can predict learning proficiency. The long-term goal is to better elucidate the contribution of the glutamatergic system underlying age-related cognitive deficits. The overall objective is to demonstrate that 1H fMRS assessment of task-dependent changes in brain Glu can be harnessed for early prediction of the impending decline in a brain system central to AD. The overarching goal of this proposal is to investigate the relationship between Glu modulation and memory efficiency. The central hypothesis is that baseline levels of Glu, and Glu modulation, will be lower in the elderly, and will be positively correlated with their performance. Guided by strong preliminary data, the hypothesis will be tested by pursuing the following specific aims: 1) Identify the effect of age and basal Glu on associative learning/memory, 2) Determine the effect of age on task-related Glu-modulation in the HC; 3) Investigate whether age-differences in hippocampal Glu modulation during encoding are related to those in learning efficiency. Under these aims 1H fMRS, determined a feasible technique in the applicant?s lab, will be used and extended to healthy old adults. Analyses will be conducted to identify a relationship between age-differences in Glu modulation and memory performance. Extant studies examining age-effects on Glu have done so using a non-task-active, static approach. The innovative approach here suggests the utility of variation in task-mediated Glu modulation as an early harbinger of age-related cognitive decline. The proposed research is significant, as it is expected to contribute to, and advance, the search for reliable functional neural biomarkers of neuro-degenerative disorders, and help track cognitive changes. Investigation of age-effects on the dynamics of Glu, an important neurotransmitter, will help gain new insights on age-differences in neurotransmission capacity and provide an effective framework to test better-targeted therapies to mitigate impending cognitive decline.